Impact of social factors on breast cancer biology in African-American women

社会因素对非裔美国女性乳腺癌生物学的影响

• 批准号: 10213668
• 负责人: Seema Singh
• 金额: $ 60.36万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213668
• 关键词: Affect; African American; Age; Alabama; Behavior; Behavioral; Biological; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Risk Factor; Breast Cancer Treatment; Cancer Biology; Cancer Control; Catchment Area; Cells; Chronic; Clinical; Clinical Management; County; Data; Development; Diagnosis; Disease; Epidemiology; Epigenetic Process; Evaluation; Exhibits; Female; Florida; Gene Expression; Gene Expression Regulation; Gene-Modified; Genes; Genetic Transcription; Global Change; Growth; Health; Hormones; Household; Human Biology; Hydrocortisone; IL6 gene; Immune; Inflammation; Inflammatory; Institutes; Intervention; Leptin; Link; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Mediating; MicroRNAs; Minority Groups; Mississippi; Modification; Morphology; Outcome; Pathogenesis; Pathway interactions; Patients; Phenotype; Physiological; Population; Poverty; Prevention; Prognosis; Publishing; Recurrence; Regulation; Regulator Genes; Reporting; Research; Role; Sampling; Serum; Shoulder; Socioeconomic Factors; Socioeconomic Status; Stress; Testing; Translating; Tumor Biology; Tumor Subtype; Up-Regulation; Woman; aggressive breast cancer; base; behavioral phenotyping; cancer health disparity; cancer risk; caucasian American; circulating microRNA; cytokine; differential expression; disadvantaged population; disorder risk; disparity reduction; epigenetic regulation; epigenomics; experience; gene function; health disparity; health disparity populations; high risk; human disease; improved; innovation; low socioeconomic status; macrophage; malignant breast neoplasm; minority disparity; mortality; obese person; racial and ethnic; remediation; resistin; risk prediction; social; social disadvantage; social factors; social stress; social stressor; socioeconomic disadvantage; socioeconomics; stressor; tumor

ABSTRACT African American (AA) women are more likely to be diagnosed at an early age with breast cancer (BC), have aggressive disease and experience greater mortality, compared to their Caucasian American (CA) counterparts. Socioeconomic status (SES) and social stress have long been believed to be the prime cause of such health disparities; however, it is not yet well understood how these social factors are translated into increased cancer risk, aggressive tumor-subtypes, and poor clinical outcomes. Demographic data suggest that AA women encounter more socioeconomic difficulties than CA women and social stressors impact human biology through epigenomic modifications of gene functions. MicroRNAs, which are important epigenetic modulators of gene expression and key players in human biology and disease, are known to be regulated by stress hormones/cytokines and exhibit differential expression in socially disadvantaged population. Along these lines, our published and preliminary studies have identified increased serum levels of inflammatory cytokines and stress hormones (resistin, IL6, leptin, and cortisol), and certain microRNAs (miR-511, miR-27a, and miR-33a) in AA women (with or without BC). We have also observed that treatment of BC cells and macrophages with resistin, IL6, leptin, and cortisol leads to an upregulation of miR-511, miR-27a, and miR-33a, promotes growth and malignant behavior of BC cells, and induces M2 polarization of macrophages. These compelling findings build a strong scientific premise for this project and support our hypothesis that socioeconomic hardships promote chronic inflammation and stress leading to altered serum levels of hormones and cytokines (such as resistin, IL6, leptin, and cortisol), which in turn, modulate the expression of immune-suppressive and tumor- promoting miRNAs, eventually contributing to BC pathogenesis. In four specific aims, we propose to determine global changes in circulating microRNAs in serum of AA and CA women (with or without BC) and establish their correlation with SES (low/moderate/high) (Aim 1); analyze levels of resistin, IL6, leptin, and cortisol in serum, and study their association with SES and serum miRNAs (Aim 2); examine regulation of miRNAs by resistin, IL6, leptin, and cortisol and delineate the underlying mechanisms (Aim 3); and establish the pathobiological significance of differentially-expressed miRNAs (Aim 4). Together, these studies will establish the functional association between socioeconomic health determinants and breast tumor biology, and support the role of miRNAs as epigenomic modifiers that link the social stress to biological phenotypes.

抽象的 非裔美国人（AA）妇女更有可能在乳腺癌（BC）的早期被诊断出患有 与他们的高加索裔美国人（CA）相比，侵略性疾病和更大的死亡率。 社会经济地位（SES）和社会压力长期以来一直被认为是这种健康的主要原因 差异；但是，目前尚不清楚这些社会因素是如何转化为癌症增加的 风险，侵略性肿瘤含量和临床结果差。人口统计数据表明AA妇女 遇到比妇女更多的社会经济困难，社会压力源会影响人类生物学 基因功能的表观基因组修饰。 microRNA，这是重要的基因表观遗传调节剂 已知人类生物学和疾病的表达和关键参与者受压力的调节 激素/细胞因子和社会弱势群体的表达差异。沿着这些线 我们发表的初步研究已经确定了炎症细胞因子的血清水平升高和 应力激素（抵抗素，IL6，瘦素和皮质醇）和某些microRNA（miR-511，miR-27a和miR-33a） AA妇女（有或没有BC）。我们还观察到，BC细胞和巨噬细胞的处理 抵抗素，IL6，瘦素和皮质醇导致miR-511，miR-27a和miR-33a的上调，可促进生长 BC细胞的恶性行为，并诱导巨噬细胞的M2极化。这些令人信服的发现 为该项目建立强大的科学前提，并支持我们的假设，即社会经济困难 促进慢性炎症和压力导致血清激素和细胞因子的水平改变（例如 抵抗素，IL6，瘦素和皮质醇）反过来调节免疫抑制和肿瘤的表达 促进miRNA，最终导致BC发病机理。在四个具体目标中，我们建议确定 AA和CA妇女（有或不带有BC）的血清中循环microRNA的全球变化，并建立她们的 与SES（低/中/高）相关（AIM 1）；分析血清中抵抗素，IL6，瘦素和皮质醇的水平， 并研究他们与SES和血清miRNA的关联（AIM 2）；检查通过抵抗蛋白IL6对miRNA的调节 瘦素，皮质醇和描述基本机制（AIM 3）；并建立病理学 差异表达的miRNA的意义（AIM 4）。这些研究将共同​​建立功能 社会经济健康决定因素与乳腺肿瘤生物学之间的关联，并支持 miRNA是将社会压力与生物学表型联系起来的表观基因组修饰剂。